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BACKGROUND: Histopathological and molecular features have been proposed to hold prognostic information, but few have been validated. The aim of this retrospective study was to validate the Genetic And Morphological Evaluation ('GAME') score and assess the impact of histological characteristics on the prognosis in patients with colorectal liver metastases. METHODS: Data were collected from 176 patients with metastatic colorectal cancer undergoing liver resection at Hospital de la Santa Creu i Sant Pau. Patients were classified into Genetic And Morphological Evaluation score groups and relapse-free survival and overall survival were calculated. Histopathological changes in colorectal liver metastases were documented and prognostic variables were selected to create a post-surgery score, called the Histopathological, Clinical, And Molecular ('HICAM') score. RESULTS: Regarding the Genetic And Morphological Evaluation score, the high-risk group had a median relapse-free survival of 8.8 months, compared with 20.5 months for the low-risk group (P = 0.005), and the high-risk group had a median overall survival of 37.8 months, compared with 67.0 months for the low-risk group (P = 0.005). Histological examination of 144 liver samples showed that the desertic immune phenotype was associated with worse overall survival in the multivariable analysis (P = 0.020). The Histopathological, Clinical, And Molecular score variables were age at diagnosis, tumour burden score, carcinoembryonic antigen levels greater than or equal to 20â ng/ml, primary tumour resection, TNM stage at diagnosis, molecular status, histopathological growth patterns, and immune phenotypes of the liver. The high-risk group had a median relapse-free survival of 8.4 months, compared with 20.4 months for the low-risk group (P < 0.001), and a median overall survival of 30.4 months, compared with 105.0 months for the low-risk group (P < 0.001). CONCLUSION: The Genetic And Morphological Evaluation score was validated as a preoperative prognostic tool to predict candidacy for liver resection. The Histopathological, Clinical, And Molecular score could be useful to assess adjuvant treatment after hepatic resection.
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Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Estudos Retrospectivos , Neoplasias Colorretais/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , HepatectomiaRESUMO
BACKGROUND: Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. METHODS: We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). RESULTS: We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. CONCLUSIONS: ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.
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Biomarcadores Tumorais , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Tumores do Estroma Gastrointestinal/genética , Adulto , Idoso , Éxons , Feminino , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Reação em Cadeia da Polimerase , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carga TumoralRESUMO
BACKGROUND: Patients harbouring the UGT1A1*28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1*1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients. METHODS: Eighty-two patients with the UGT1A1*1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1*28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300 mg/m2 for UGT1A1*1/*1 and 260 mg/m2 for *1/*28 patients. In the control group, the dose was 180 mg/m2. We analysed the overall response rate (ORR), toxicity, and survival. RESULTS: The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p = 0.001 OR: 1.73 [95% CI:1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3-4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found. CONCLUSIONS: Patients with the UGT1A1*1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Glucuronosiltransferase/genética , Irinotecano/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Genótipo , Humanos , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Testes FarmacogenômicosRESUMO
The role of vascular endothelial growth factor (VEGF) gene polymorphisms in the prognosis of colon cancer prognosis remains unclear. We evaluated the influence of 28 single-nucleotide polymorphisms in 12 genes in the VEGF pathway on the prognosis of 347 patients with stage II-III colon cancer. We found that rs9513070 (VEGFR1) and rs1137282 (KRAS) were associated with overall survival in stage II colon cancer patients (p = 0.025 and p = 0.001, respectively). When primary tumor location was considered, rs9513070 was also associated with relapse-free and overall survival (p = 0.033 and p = 0.031, respectively) in left colon cancer patients. Additionally, rs35251833 in the ITGAV gene correlated with relapse-free survival (p = 0.032). This study provides evidence that germline polymorphisms in VEGFR1, KRAS and ITGAV genes are associated with prognosis in stages II-III colon cancer patients. As stage and tumor location are correlated with prognosis, future genetic studies should stratify colon cancer patients according to these parameters.
Assuntos
Neoplasias do Colo/genética , Integrina alfaV/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Intervalo Livre de Progressão , Estudos RetrospectivosRESUMO
Severe irinotecan-induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side-effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan-metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss-of-function allele in the toxicity profile of these patients. Three-hundred and eight metastatic colorectal cancer patients treated with an irinotecan-containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan-induced toxicity.
Assuntos
Astenia/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Citocromo P-450 CYP3A/genética , Diarreia/induzido quimicamente , Glucuronosiltransferase/genética , Irinotecano/efeitos adversos , Neutropenia/induzido quimicamente , Variantes Farmacogenômicos , Inibidores da Topoisomerase I/efeitos adversos , Idoso , Astenia/diagnóstico , Astenia/genética , Neoplasias Colorretais/patologia , Citocromo P-450 CYP3A/metabolismo , Diarreia/diagnóstico , Diarreia/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Glucuronosiltransferase/metabolismo , Heterozigoto , Humanos , Masculino , Neutropenia/diagnóstico , Neutropenia/genética , Fenótipo , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Poor long-term survival in localized high-risk soft tissue sarcomas (STSs) of the extremities and trunk highlights the need to identify new prognostic factors. CXCR4 is a chemokine receptor involved in tumor progression, angiogenesis, and metastasis. The aim of this study was to evaluate the association between CXCR4 expression in tumor tissue and survival in STSs patients treated with neoadjuvant therapy. CXCR4 expression was retrospectively determined by immunohistochemical analysis in serial specimens including initial biopsies, tumors post-neoadjuvant treatment, and tumors after relapse. We found that a positive cytoplasmatic expression of CXCR4 in tumors after neoadjuvant treatment was a predictor of poor recurrence-free survival (RFS) (p = 0.003) and overall survival (p = 0.019) in synovial sarcomas. We also found that positive nuclear CXCR4 expression in the initial biopsies was associated with poor RFS (p = 0.022) in undifferentiated pleomorphic sarcomas. In conclusion, our study adds to the evidence that CXCR4 expression in tumor tissue is a promising prognostic factor for STSs.
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BACKGROUND: The value of total body skin examination (TBSE) for skin cancer screening is controversial. OBJECTIVE: We sought to determine whether TBSE could be helpful in patients with focused skin symptoms who would not otherwise have undergone TBSE. METHODS: In a prospective, multicenter, cross-sectional study consecutive adult patients were recruited during a period of 18 months. Physicians first inspected problem areas and uncovered areas and then performed TBSE. Equivocal lesions detected in both steps were excised or biopsied. Primary outcomes were the absolute and relative risks of missing skin cancer and the number of patients needed to examine to detect melanoma or another malignancy. A secondary outcome was the proportion of false-positive results obtained by TBSE. RESULTS: We examined 14,381 patients and detected 40 (0.3%) patients with melanoma and 299 (2.1%) with at least one nonmelanoma skin cancer by TBSE. In 195 (1.3%) patients equivocal lesions found by TBSE turned out to be benign. We calculated that 47 patients need to be examined by TBSE to find one skin malignancy and 400 patients to detect one melanoma. The risk of missing one malignancy if not performing TBSE was 2.17% (95% confidence interval 1.25-3.74). Factors significantly increasing the chance to find a skin cancer were age, male gender, previous nonmelanoma skin cancer, fair skin type, skin tumor as the reason for consultation, and presence of an equivocal lesion on problem/uncovered areas. LIMITATIONS: The impact of TBSE on skin cancer mortality was not evaluated. CONCLUSIONS: TBSE improves skin cancer detection in patients with focused skin symptoms and shows a low rate of false-positive results.
Assuntos
Detecção Precoce de Câncer/métodos , Exame Físico/métodos , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Biópsia , Estudos Transversais , Dermoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Dermatopatias/diagnósticoRESUMO
OBJECTIVE: To determine the prevalence of loss-of-function variants in the dihydropyrimidine dehydrogenase gene in patients with gastrointestinal neoplasms, assess their clinical relevance, and evaluate the implementation of a multidisciplinary circuit at three months from its implementation. METHOD: This is a descriptive, observational and retrospective study, which included adult patients with gastrointestinal cancer treated at a tertiary university hospital who underwent dihydropyrimidine dehydrogenase genotyping between September 2019 and December 2020. The variables collected were sex, age, type of cancer, location, stage, treatment received, indication of treatment and degree of toxicity developed during the first three cycles. The genotyped variants were rs3918290 (c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798 (c.2846A>T) and rs75017182 (c.1129-5923C>G). RESULTS: A total of 115 patients were included. The frequency of heterozygous dihydropyrimidine dehydrogenase variant carriers was 9.6% (11 patients). The most frequently identified variant was rs75017182 (6 patients). The second most common variant was rs67376798 (3 patients), followed by rs3918290 (2 patients). No patients presented with the rs55886062 variant. Two of the dihydropyrimidine dehydrogenase carriers developed grade 3-5 toxicity after the first cycle of a regimen that included fluoropyrimidines. Both received full doses of fluoropyrimidine, since their dihydropyrimidine dehydrogenase genotype was unknown before treatment initiation. None of the dihydropyrimidine dehydrogenase carriers who began treatment with a reduced dose of fluoropyrimidine experienced grade 3-5 toxicity. Since the creation in October 2020 of a multidisciplinary team, with the active participation of hospital pharmacists, the monthly average of dihydropyrimidine dehydrogenase genotyping studies has increased from 6.4 (January-October) to 17.5 (November-December). CONCLUSIONS: The present study shows a relatively high prevalence of loss-of- function variants in the dihydropyrimidine dehydrogenase gene as well as the importance of genotyping such variants before starting a treatment with fluoropyrimidines. Hospital pharmacists can contribute to the implementation of pharmacogenetics in daily clinical practice in a tertiary hospital.
OBJETIVO: Determinar la prevalencia de variantes de pérdida de función en el gen de la dihidropirimidina deshidrogenasa (DPYD) en pacientes con tumores digestivos, valorar su relevancia clínica y evaluar la implementación de un circuito multidisciplinar tras tres meses de funcionamiento.Método: Estudio descriptivo, observacional y retrospectivo donde se incluyeron los pacientes adultos afectos de tumores digestivos, atendidos en un hospital universitario de tercer nivel, a los que se había afectuado el genotipado de DPYD entre septiembre de 2019 y diciembre de 2020. Las variables recogidas fueron sexo, edad, tipo de cáncer, localización, estadio, tratamiento recibido, indicación del tratamiento y grado de toxicidad desarrollado durante los tres primeros ciclos. Se genotiparon las variantes rs3918290 (c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798 (c.2846A>T) y rs75017182 (c.1129-5923C>G). RESULTADOS: Se incluyeron 115 pacientes. La frecuencia de portadores en heterocigosis de variantes del gen DPYD fue del 9,6% (11 pacientes). La variante más frecuentemente identificada fue el rs75017182 (6 pacientes). La segunda variante más frecuente fue el rs67376798 (3 pacientes), seguida del rs3918290 (2 pacientes). Ningún paciente presentó la variante rs55886062. Dos de los pacientes portadores desarrollaron toxicidad grados 3-5 tras el primer ciclo de un esquema que incluía fluoropirimidinas. Ambos recibieron dosis plenas de fluoropirimidina, puesto que no se conocía el genotipo de DPYD antes de iniciar el tratamiento. Ninguno de los pacientes portadores que tmpezó el tratamiento con una dosis reducida de fluoropirimidina experimentó toxicidad grados 3-5. Desde la creación en octubre de 2020 de un equipo multidisciplinar, con participación activa del farmacéutico hospitalario, se ha incrementado el número de estudios de genotipado de DPYD de una media de 6,4 estudios mensuales (enero-octubre) a 17,5 (noviembre-diciembre). CONCLUSIONES: Nuestro estudio muestra la relativamente elevada prevalencia de variantes de pérdida de función en el gen DPYD, así como la importancia de genotiparlas antes de empezar un esquema de tratamiento que contenga fluoropirimidinas. El farmacéutico hospitalario puede contribuir a la implementación de la farmacogenética en la práctica clínica diaria en un hospital de tercer nivel.
Assuntos
Di-Hidrouracila Desidrogenase (NADP) , Neoplasias Gastrointestinais , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Humanos , Estudos RetrospectivosRESUMO
BACKGROUND: Chronic myelogenous leukemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. The hallmark genetic abnormality of CML is a chimeric BCR/ABL1 fusion gene resulting from the Philadelphia chromosome rearrangement t(9;22)(q34;q11). Clinical and laboratory studies indicate that the BCR/ABL1 fusion protein is essential for initiation, maintenance and progression of CML, yet the event(s) driving the transformation from chronic phase to blast phase are poorly understood. RESULTS: Here we report multiple genome aberrations in a collection of 78 CML and 14 control samples by oligonucleotide array comparative genomic hybridization. We found a unique signature of genome deletions within the immunoglobulin heavy chain (IGH) and T cell receptor regions (TCR), frequently accompanied by concomitant loss of sequences within the short arm regions of chromosomes 7 and 9, including IKZF1, HOXA7, CDKN2A/2B, MLLT3, IFNA/B, RNF38, PAX5, JMJD2C and PDCD1LG2 genes. CONCLUSIONS: None of these genome losses were detected in any of the CML samples with myeloid transformation, chronic phase or controls, indicating that their presence is obligatory for the development of a malignant clone with a lymphoid phenotype. Notably, the coincidental deletions at IGH and TCR regions appear to precede the loss of IKZF1 and/or p16 genes in CML indicating a possible involvement of RAG in these deletions.
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Crise Blástica/genética , Genes Codificadores dos Receptores de Linfócitos T , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Deleção de Sequência , Crise Blástica/imunologia , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 9 , Hibridização Genômica Comparativa , Biologia Computacional , Genes p16 , Humanos , Fator de Transcrição Ikaros/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (P-gp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan.
RESUMO
BACKGROUND: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. PATIENTS AND METHODS: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. RESULTS: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. CONCLUSIONS: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.
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Two patients with the characteristic high human herpesvirus 6 (HHV-6) DNA loads in peripheral blood caused by chromosomally integrated (CI) virus received a haematopoietic stem cell transplant (HSCT) from a donor without CI HHV-6. Both patients died in consequence of cytomegalovirus (CMV) pneumonitis. At autopsy, high amounts of CMV DNA were detected in lungs but at much lower levels in other organs. In contrast HHV-6 DNA was detected at high levels throughout the organs with the exception of donor-derived haematopoietic tissue. In individuals with chromosomal integration, HHV-6 DNA is found in every tissue of recipient origin indicating inheritance through the germ line.
Assuntos
Cromossomos Humanos/virologia , DNA Viral/análise , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 6/genética , Infecções por Roseolovirus/virologia , Integração Viral/genética , Adulto , Criança , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/mortalidade , Evolução Fatal , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/virologia , Pulmão/virologia , Masculino , Pneumonia/mortalidade , Pneumonia/virologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Infecções por Roseolovirus/genéticaRESUMO
Fluorescent in situ hybridization (FISH) was used to investigate the chromosomal integration sites of human herpesvirus 6 (HHV-6) in phytohemagglutinin-stimulated leukocytes and B lymphocytes from Epstein-Barr virus transformed lymphoblastoid cell lines (LCLs). Five different chromosomal integration sites were found in nine individuals. Only one site was identified in each individual, each site was in the vicinity of the telomeric region and was on either the p or q arm of only one of the two chromosome homologues. The sites were 9q34.3, 10q26.3, 11p15.5, 17p13.3, and 19q 13.4, of which three have not been previously identified. For 9q34.3 the site of integration was further mapped using a locus-specific probe for 9q34.3 together with a pan-telomeric probe and both co-localized with the HHV-6 signal. Similarly an arm-specific telomeric probe for 19q co-localized with the HHV-6 signal. It was therefore concluded that the site of integration is actually within the telomere. The number of viral DNA copies/cell was calculated in blood, LCL cells and hair follicles and was one or more in every case for each of the nine individuals. This result was confirmed by FISH where 100% of cells gave an HHV-6 signal. These findings add to previous reports suggesting that integrated HHV-6 DNA is found in every cell in the body and transmitted vertically. Finally, including our data, worldwide seven different chromosomal sites of HHV-6 integration have now been identified. Large epidemiological studies of chromosomal integration are required to identify further telomeric sites, geographical or racial variation and possible clinical consequences.
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Herpesvirus Humano 6/fisiologia , Telômero/virologia , Integração Viral , Adolescente , Adulto , Cromossomos Humanos/virologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Leucócitos/virologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIMS: To evaluate the association of psoriasis with selected medical conditions and a number of drugs used before diagnosis. METHODS: Multicenter case-control study involving outpatient services of 20 general and teaching hospitals. Entry criteria for cases were a first diagnosis of psoriasis made by a dermatologist and a history of skin manifestations of no more than 2 years after the reported onset of the disease. Controls were the first eligible dermatological patients observed on randomly selected days in the same centers as cases. A total of 560 cases and 690 controls were recruited. RESULTS: The odds ratio (OR) of psoriasis was 0.8 (95% confidence interval, CI, 0.5-1.3) in hypertensive subjects, 1.1 (95% CI 0.6-2.0) in diabetics and 1.1 (95% CI 0.7-1.7) in hyperlipidemic subjects. Histamine 2 receptor antagonist exposure was negatively associated with psoriasis: OR 0.3 (95% CI 0.1-0.8). CONCLUSION: Our study rules out a strong association of psoriasis at its first ever diagnosis with common chronic conditions. The reported associations of psoriasis with relatively common conditions such as diabetes mellitus, hypertension and hyperlipidemia may represent a late effect of well-known risk factors for psoriasis such as smoking and overweight or reflect factors related to the long course of psoriasis itself.
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Antagonistas dos Receptores Histamínicos/efeitos adversos , Psoríase/epidemiologia , Psoríase/etiologia , Adulto , Distribuição por Idade , Idoso , Intervalos de Confiança , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Distribuição por SexoAssuntos
Produtos Biológicos/efeitos adversos , Candidíase Bucal/induzido quimicamente , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Candidíase Bucal/microbiologia , Estudos de Casos e Controles , Dentaduras/efeitos adversos , Dentaduras/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Higiene Bucal , Psoríase/imunologia , Fatores de Risco , Fumar/efeitos adversosAssuntos
Carbonato de Cálcio/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Dermatite Perioral/induzido quimicamente , Docentes , Dermatoses da Mão/induzido quimicamente , Níquel/efeitos adversos , Doenças Profissionais/induzido quimicamente , Adulto , Carbonato de Cálcio/química , Dermatite Alérgica de Contato/diagnóstico , Dermatite Perioral/diagnóstico , Feminino , Dermatoses da Mão/diagnóstico , Humanos , Níquel/análise , Doenças Profissionais/diagnóstico , Exposição Ocupacional , Testes do Emplastro , Espectrofotometria AtômicaAssuntos
Anticorpos Monoclonais/efeitos adversos , Artrite Psoriásica/etiologia , Fármacos Dermatológicos/efeitos adversos , Psoríase/tratamento farmacológico , Administração Tópica , Adolescente , Adulto , Anticorpos Monoclonais Humanizados , Artrite Psoriásica/complicações , Artrite Psoriásica/patologia , Feminino , Humanos , Articulações/efeitos dos fármacos , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Recall e Retirada de Produto , Suspensão de TratamentoRESUMO
We conducted a case-control study to analyse the association of psoriasis of recent onset with smoking habits, body mass index (BMI) and stressful life events. Cases (n=560; median age 38) were patients with a first diagnosis of psoriasis and a history of skin manifestations of no longer than two years after the reported disease onset. Patients with a new diagnosis of skin diseases other than psoriasis (n=690; median age 36) were selected as controls. The risk of psoriasis was higher in ex- and current smokers than in never-smokers, the relative risk estimates (OR) being 1.9 for ex-smokers and 1.7 for smokers. Smoking was strongly associated with pustular lesions (32 patients, OR=5.3 for smokers). The frequency of psoriasis varied significantly in relation to a family history of psoriasis in first degree relatives, BMI (OR=1.6 and 1.9 for over weighted, BMI 26-29, and obese, BMI >/= 30, respectively) and stressful life event score (compared to the lower index quartile, the OR being 2.2 for index values >/=115). Risk estimates, when taking into consideration the combined effect of these factors with smoking habits, were consistent with a multiplicative model of risk combination with no significant statistical interaction.
Assuntos
Índice de Massa Corporal , Psoríase/etiologia , Fumar/efeitos adversos , Estresse Psicológico/complicações , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
INTRODUCTION: The chemoprevention refers to the use of various types of chemical agents for preventing carcinogenic progression. Systemic retinoids are the most studied chemopreventive agents due to their capacity to regulate cell proliferation and their demonstrated efficacy in several clinical studies. OBJECTIVES: The aim of the authors was to give precise indications regarding the use of the systemic retinoid in the chemoprevention of non-melanoma skin cancer (NMSC). METHODS: The authors reviewed the literature found through a search to MEDLINE (from 2001 to December 2011). RESULTS: Both acitretin and isotretinoin are effective for the prevention of NMSC. Isotretinoin is preferred in xeroderma pigmentosum and nevoid basal cell carcinoma syndrome, whereas acitretin is more used in transplant recipients, psoriasis and severe sun damage. CONCLUSION: Despite numerous studies of the literature concerning retinoids in chemoprevention of NMSC, precise details of the type of retinoid to use, dosage and the duration of this preventive treatment and how to manage side effects in the case of long-lasting treatment are still not uniform and comparable. Moreover, neither guidelines nor approval by Food and Drug Administration exist to regulate the use of retinoids in chemoprevention.